Bacterial pneumonia is a leading cause of morbidity and mortality in the United States. Infection is initiated by inhaled microorganisms that are deposited in the aqueous lining film which coats the alveolar epithelium. This compartment contains pulmonary surfactant, a mixture of phospholipids and proteins that maintains alveolar patency by reducing surface tension forces at the dir-liquid interface. Recent data suggests that surfactant protein A (SP-A), an abundant oligomeric glycoprotein in the distal airspaces, is also an acute phase reactant that functions as a major preimmune opsonin and lipopolysaccharide (LPs)-binding protein in the lung. The response of the alveolar macrophage (AM), the predominant inflammatory cell in the alveolar lumen, to microbes and microbial products must be tightly regulated to promote effective clearance while avoiding inappropriate inflammatory responses that may compromise gas exchange. Preliminary data presented herein suggests that SP-A enhances the clearance of pulmonary bacterial infections in mice and regulates the interaction of LPS with macrophages. Using recombinant SP-As with targeted mutations in critical structural domains and transgenic mice that overexpress rat and mutant of SP-A, we will test the hypothesis that SP-A modulates the inflammatory response of the lung to LPS and pathogenic microorganisms in the lung, and in the clearance of LPS and microbial infection from the airspace. Specific aim #2 will examine the structural domains of SP- A that mediate binding to LPS and bacterial microorganisms, the production of proinflammatory mediators and nitric oxide, and the clearance of LPS and microorganisms from the airspace. These studies will elucidate the role of SP-A in the innate immune defense of the lung, and may assist in the design of optimal antimicrobial strategies.